Heart failure with preserved ejection fraction: fighting misconceptions for a new approach

Abstracts

Durante as últimas décadas, a insuficiência cardíaca com fração de ejeção preservada (ICFEP) foi alvo de menor atenção por parte das comunidades médica e científica, o que levou ao aparecimento de um conjunto de equívocos relativamente às suas características, diagnóstico e abordagem terapêutica. Nos últimos anos surgiram novos estudos que alteraram os conceitos classicamente associados à ICFEP, contribuindo para uma nova visão dessa doença. Com esta revisão pretendemos abordar as mais recentes evidências existentes na área da ICFEP e combater os principais equívocos a ela associados, de forma a melhorar a sua abordagem diagnóstica e terapêutica. Temos hoje vários dados que demonstram que a ICFEP é uma entidade que necessita de uma abordagem clínica distinta da utilizada na insuficiência cardíaca sistólica (ICS). A ICFEP deixou de ser vista como uma doença "benigna", porque está associada a um mau prognóstico e a uma elevada prevalência. A sua fisiopatologia é complexa, não está totalmente esclarecida e, para além da disfunção diastólica, foram recentemente descobertos outros fatores, cardíacos e extracardíacos, que estão também implicados no seu aparecimento. Dispomos hoje de critérios objetivos para o seu diagnóstico, sobretudo recorrendo aos novos parâmetros ecocardiográficos de avaliação da função diastólica, nomeadamente ao cálculo da relação E/e' obtida por meio do Doppler tecidual. Finalmente, o tratamento da ICFEP continua a ser uma incógnita, porque não dispomos atualmente de nenhuma estratégia terapêutica capaz de alterar o prognóstico da ICFEP. Desse modo, abordaremos também os potenciais novos alvos terapêuticos que poderão revolucionar o tratamento futuro da ICFEP.

Insuficiência cardíaca; diástole; função ventricular; envelhecimento da população

Durante las últimas décadas, la insuficiencia cardíaca con fracción de eyección preservada (ICFEP) fue blanco de menor atención por parte de las comunidades médica y científica, lo que llevó a la aparición de un conjunto de equívocos relativos a sus características, diagnóstico y abordaje terapéutico. En los últimos años surgieron nuevos estudios que alteraron los conceptos clásicamente asociados a la ICFEP, contribuyendo a una nueva visión de esa enfermedad. Con esta revisión pretendemos abordar las más recientes evidencias existentes en el área de la ICFEP y combatir los principales equívocos asociados a ella, para mejorar su abordaje diagnóstico y terapéutico. Tenemos hoy varios datos que demuestran que la ICFEP es una entidad que necesita un abordaje clínico distinto del utilizado en la insuficiencia cardíaca sistólica (ICS). La ICFEP dejó de ser vista como una enfermedad "benigna", porque está asociada a un mal pronóstico y a una elevada prevalencia. Su fisiopatología es compleja, no está totalmente aclarada y, más allá de la disfunción diastólica, fueron descubiertos recientemente otros factores, cardíacos y extracardíacos, que están también implicados en su aparición. Disponemos hoy de criterios objetivos para su diagnóstico, sobre todo recurriendo a los nuevos parámetros ecocardiográficos de evaluación de la función diastólica, principalmente al cálculo de la relación E/e' obtenida por medio del Doppler tisular. Finalmente, el tratamiento de la ICFEP continúa siendo una incógnita, porque no disponemos actualmente de ninguna estrategia terapéutica capaz de alterar el pronóstico de la ICFEP. De ese modo, abordaremos también los potenciales nuevos blancos terapéuticos que podrán revolucionar el tratamiento futuro de la ICFEP.

Insuficiencia cardíaca; diástole; función ventricular; envejecimiento de la población

REVIEW ARTICLE

^IServiço de Fisiologia da Faculdade de Medicina do Porto

^IIServiço de Cardiologia do Centro Hospitalar de Vila Nova de Gaia

^IIICentro de Cirurgia Torácica do Hospital de São João, Porto - Portugal

Mailing address

ABSTRACT

Over the last decades, heart failure with preserved ejection fraction (HFpEF) has received less attention by the medical and scientific communities, which led to the emergence of a number of misconceptions concerning its characteristics, diagnostic and therapeutic approach.

In recent years, new studies have changed the concepts traditionally associated with HFpEF, contributing to a new view towards this disease. This review is intended to discuss the latest evidence on HFpEF and to fight the main misconceptions associated with it in order to improve its diagnostic and therapeutic approach.

Today we have several data showing that HFpEF is a condition that requires a different clinical approach from that used in systolic heart failure (SHF). HFpEF is no longer seen as a "benign" disease because it is associated with a poor prognosis and high prevalence. Its pathophysiology is complex and not fully clarified. In addition to diastolic dysfunction, we now know that other cardiac and extracardiac factors are also involved in its onset and progression. Using recent consensus guidelines we have objective criteria for its diagnosis, especially by using the new echocardiographic parameters for assessing diastolic function, including the E/e' ratio obtained by tissue Doppler. Finally, treatment of HFpEF remains unknown, because no therapeutic strategy has been shown to improve HFpEF prognosis. Thus, in this review we will also discuss the potentially new therapeutic targets for HFpEF.

Keywords: Heart failure/therapy; stroke volume; ventricular function; demographic aging.

Introduction

Heart failure (HF) represents a major and growing public health problem, affecting 2% - 3% of adults in developed countries¹.

Patients with heart failure are classically divided into two groups: those with HF with preserved ejection fraction (HFpEF), also called diastolic HF (DHF) and those with HF and reduced ejection fraction (HFrEF), better known as systolic HF (SHF)¹.

In recent decades, HFpEF has received much less attention from medical and scientific communities, a situation that is finally starting to change. Such lack of attention resulted in the gradual emergence, within the medical community, of a series of misconceptions and dogmas concerning the epidemiology, diagnosis, pathophysiology and treatment of HFpEF.

With this review, we intend to explore and tackle the major misconceptions associated with HFpEF. We will discuss the latest evidence concerning HFpEF, providing a new view on this complex syndrome, in order to improve its clinical and therapeutic approach.

Frequent misconceptions in heart failure with preserved ejection fraction

Misconception 1: HFpEF is a benign condition

Until recently, HFpEF had been considered an essentially "benign" disease associated with a better prognosis. Epidemiological studies have shown that the prognosis for these patients is as bad as those who have systolic HF (SHF)^2,3. Patients with HFpEF have mortality rates of 29% after one year (versus 32% in patients with systolic HF), and 65% after five years (versus 68%)³.

The morbidity of HFpEF is also very high, requiring frequent admissions and a significant consumption of resources^4,5. Once admitted due to HF, these patients have a high rate of readmission of 50% after one year⁵.

Equally worrying is the evidence showing that the survival of patients with HFpEF has not been improving in recent decades, unlike what has been observed in patients with systolic HF⁶. Such observation is probably related to the fact that the management and treatment of these patients are not producing the desired effects, probably due to various misconceptions concerning HFpEF.

Misconception 2: diastolic HF is an uncommon syndrome

A second misconception in HFpEF is to think that this is a clinical condition that is less common than the SHF. This is quite the opposite! We know today that HFpEF is responsible for about 50% of all patients admitted with HF, a proportion that increases with age^2,4,6-8. Moreover, in the last two decades the proportion of patients with HFpEF increased from 38% to 54% out of cases of HF⁶, a proportion that will continue to rise due to the progressive aging of population and expected increase in the prevalence of hypertension, obesity and diabetes.

Misconception 3: diastolic HF and systolic HF are the same condition

The classical separation of HF in HFpEF is questioned by several authors who argue that these relate to the same condition, albeit with different phenotypes^9,10.

However, there are many demographic, epidemiological, histological, molecular and structural arguments, as well as some relating to ventricular function and even therapeutic effectiveness, which seem to clearly indicate that these two conditions are quite different (Table 1)^6,11.

Regarding the characteristics of the population, patients with HFpEF are older, often female, and have a high prevalence of hypertension, diabetes and obesity, as well as various comorbidities such as atrial fibrillation, renal failure and anemia^2-4,7,12,13 (Table 1).

The hearts of patients with systolic HF and HFpEF also have significant differences in terms of structure and ventricular function (Table 1). The hearts of patients with SHF present an eccentric ventricular modeling with increased diastolic volumes and the main anomaly occurs in LV systolic properties¹⁴ (Figure 1). By contrast, patients with HFpEF present as concentric remodeling, the volumes are normal or even reduced, and the main change occurs in the diastolic properties, with delayed relaxation and/or increased ventricular stiffness^14-16 (Figure 1 and Table 1).

Other recently published studies have also shown differences at histological and molecular level. For example, analysis of endomyocardial biopsies revealed that cardiomyocytes of patients with HFpEF are structurally different, with larger diameters, greater stiffness and increased density of myofilaments, compared to patients with ICS¹⁷. Significant differences were also discovered at the molecular level. Titin is a molecule found inside the sarcomere which, given its elastic properties, is the main determinant of the stiffness of cardiomyocytes. It was found that in patients with HFpEF there is a change in the expression of the isoforms of this molecule - with increased expression of the stiffer isoform - or its degree of phosphorylation, which contributes to the increase in ventricular stiffness observed in these patients^17,18. Patients with HFpEF and systolic HF also have significant differences in fibrosis and extracellular collagen matrix, due to distinct patterns of extracellular matrix metalloproteinases (MMP) and tissue inhibitors of such metalloproteinases (TIMP) activation. While in HFpEF there is a decreased degradation of extracellular matrix (resulting in increased ventricular stiffness), in dilated cardiomyopathy there is an increased matrix degradation^19,20. In the HFpEF, diastolic dysfunction ca occur due to changes in the passive properties of the ventricle - particularly increased ventricular stiffness - or due to alterations in myocardial relaxation. The delay in myocardial realaxation seen in patients with HFpEF is caused by changes in calcium kinetics, especially by reduced activity of SERCA₂, the main protein responsible for the reuptake of calcium back into the sarcoplasmic reticulum²¹.

Finally, strong arguments related to the response to pharmacological therapy justify the separation of these two conditions. Few clinical trials performed to date on HFpEF reveal that these patients do not respond as well to therapy commonly used in systolic HF, suggesting that different pathophysiological mechanisms operate in these two conditions.

These differences mean that the therapeutic approach to HFpEF must be different from that used in systolic HF, as prescribed in the guidelines for heart failure^1,22.

Misconception 4: diastolic dysfunction is the only abnormality involved in HFpEF

The patophysiology of HFpEF is not totally understood, mainly because HFpEF affects an heterogeneous group of patients where different pathophysiological mechanisms may have a different relative importance.

Diastolic dysfunction plays a central role in the pathophysiology of this condition, since most patients present delayed myocardial relaxation and/or increased ventricular stiffness²³. This is why HFpEF is often referred to as diastolic HF. More recently, after the discovery of other mechanisms that appear to contribute to the pathophysiology of this condition, the expression diastolic HF was replaced by a more general term: HFpEF ^1,24.

On the other hand, we know that LV diastolic dysfunction, by itself, does not seem to be enough to cause the clinical picture of heart failure. There is an important group of patients who have diastolic dysfunction, although they remain asymptomatic and without HF²⁵. Moreover, the prevalence of diastolic dysfunction in the general population (present in up to 25% of the population²⁶) is much higher than the prevalence of HF. However, it remains to be explained why some patients with diastolic dysfunction have HFpEF, while others remain asymptomatic.

Beyond diastolic dysfunction: contribution of other pathophysiological mechanisms

Several studies have recently demonstrated that the pathophysiology of HFpEF involves other mechanisms, including "cardiac" and "extracardiac" factors (Figure 2)^27,28. The explanation for the symptomatic difference among patients with asymptomatic diastolic dysfunction and HFpEF may be due to the simultaneous existence of these additional pathophysiological abnormalities only in patients with HFpEF.

Among "extracardiac" abnormalities found in HFpEF, particular emphasis has been placed on the abnormalities found in the arterial vessels, including increased arterial stiffness, changes in ventricular-arterial coupling^29,30, endothelial dysfunction and reduced vasodilator reserve ³¹.

There are other extracardiac factors potentially involved in HFpEF. It was found that in these patients, increased ventricular filling pressure is also due to an increased effective circulating volume due to increased sodium and water retention in the kidneys³². It should be stressed that in HFpEF, due to the simultaneous increase of ventricular and arterial stiffness, patients are very sensitive to small changes in the "central" volume¹⁶.

Recently, new "cardiac" factors have been found to contribute to HFpEF pathophysiology, such as chronotropic incompetence³¹ and changes in ventricular stretching, radial deformation and twisting, evaluated by speckle tracking analysis³³.

Finally, HFpEF patophysiology is usually accessed at rest. However, several studies have shown that additional alterations occur during exercise in HFpEF patients^31,34-36.

Is systolic function completely normal in HFpEF?

By definition, HFpEF patients have a normal ejection fraction. Nevertheless, because ejection fraction is an imprecise parameter for the evaluation of minor alterations in systolic function, it has been demonstrated that patients with HFpEF also have changes in systolic function assessed by Tissue Doppler analysis^37,38. Also, a recent study has shown that in HFpEF patients important alterations in systolic function also occur especially in response to exercise³³.

Misconception 5: there are no objective criteria for the diagnosis of HFpEF

Part of the controversy and misconceptions concerning HFpEF resulted from the lack of consensus about its diagnostic criteria.

Such limitation was overcome in 2007 after the publication of a consensus document of the European Society of Cardiology with updated diagnostic criteria for HFpEF²⁴. According to this document, three prerequisites should be fulfilled simultaneously to diagnose HFpEF: 1) symptoms and signs of HF; 2) EF> 50% in a non-dilated LV (defined as LV with a end diastolic volume < 97 ml/m²); 3) evidence of high LV filling pressures.

The demonstration of high LV filling pressures can be made by invasive hemodynamic evaluation (which is the gold-standard method, but is difficult to apply in clinical practice) or by combining several echocardiographic parameters together with natriuretic peptides quantification. By echocardiography several diastolic parameters can be obtained that allow LV filling pressures estimation³⁹. The most widely used parameter, and also the easiest to analyse, is the E/e' ratio, which is obtained from the ratio between the peak transmitral flow velocity (E wave) and the mitral annulus velocity, determined from Tissue Doppler analysis (the e' wave) (Fig. 3). When the E/e' ratio at the level of the septal wall is > 15, LV filling pressures are certainly increased, whereas a E/e' ratio < 8 represents normal LV filling pressures²⁴. However when the E/e' ratio is between 8 and 15, it is necessary to combine this value with other diastolic function echocardiographic parameters, as discussed later.

The new diagnostic algorithm of HFpEF, despite a few limitations²⁸ allowed standardizing the diagnosis of HFpEF.

Misconception 6: diastolic function evaluation by echocardiography is inaccurate and has no influence on clinical management strategies

The assessment of LV diastolic function should be an integral part of routine echocardiographic evaluation⁴⁰, especially in patients with dyspnoea and/or heart failure, due to its diagnostic²⁴ and prognostic significance⁴¹.

Initially, the diastolic function by echocardiography was mainly assessed through pulsed Doppler analysis of transmitral flow pattern. When this parameter is used alone, it is little specific, and has several limitations. This fact has led to the emergence of the (misconceived) idea that the echocardiographic assessment of diastolic function is little specific and little useful in clinical practice. Today, there are several echocardiographic parameters in the assessment of diastolic function, whose applications, advantages and limitations have been the target of a consensus document of the European and American societies of Echocardiography³⁹, which will be briefly addressed in this study (Table 2).

Pulsed Doppler transmitral inflow pattern

The analysis of transmitral flow by pulsed Doppler is easy to obtain in almost all patients (Fig. 4, A). By analyzing transmitral filling pattern, it is possible to define four degrees of diastolic dysfunction (Fig. 3).

Nevertheless, this parameter has several limitations (Table 2)³⁹ because when used alone, it is not possible to distinguish a normal pattern from a pseudonormal, which indicates a grade II diastolic dysfunction (Figure 3). Despite its limitations, when combined with other diastolic dysfunction parameters, the evaluation of the E/A ratio can be useful in clinical practice to support the diagnosis of HFpEF²⁴. and give prognostic information, when a restrictive pattern is present⁴¹.

Isovolumic relaxation time (IVRT)

This parameter, which assesses primarily the ventricular relaxation, measures the time interval between aortic valve closure and mitral valve opening (Fig. 5, panel C). The normal value of IVRT is 70-90 msec, a value that increases with delayed relaxation, but shortens when filling pressures are markedly increased³⁹.

 

Mitral flow propagation velocity (Vp)

The mitral flow propagation velocity (Vp) is evaluated according to Figure 5, panel A. When ventricular relaxation is delayed, the Vp slope is reduced.

Pulmonary vein flow velocity assessment

The pulmonary vein flow assessment can provide several measurements for diastolic function evaluation. However, the most reliable parameter is the Ar pulm - Ad mitral, which is the time difference between the duration of reversed pulmonary vein flow during atrial systole (Ar pulm) and the duration of the mitral A wave flow (Figure 5, B); when the Ar pulm - Ad mitral difference is > 30 msec, LV filling pressures are increased²⁴.

Tissue Doppler assessment at the mitral annulus and E/e' ratio

The most widely used echocardiographic parameter for diastolic function evaluation is the E/e'(see figure 4)^24,40, which is the ratio of the E wave velocity from transmitral flow divided by the e' wave velocity obtained by Doppler tissue at the mitral annulus level. By applying the pulsed tissue Doppler at the septal or lateral side of the mitral annulus, it is possible to evaluate the velocity of the mitral annulus displacement and calculate the velocity of the systolic wave (S wave), of the early diastolic wave (E', e' or Ea) and of the late diastolic wave (A', a' or Am).

Several studies have shown that E/e' ratio correlates closely with LV filling pressures, independently from ejection fraction values. When E/e' ratio at the septal side of the mitral annulus is > 15, LV filling pressures are increased, whereas an E/e' value < 8 indicates normal filling pressures. However, when the e' is evaluated at the lateral side of the mitral annulus, and not at the septal wall, a cut-off of E/e' > 12 (instead of 15) should be used, because displacement velocities are greater at the lateral side⁴².

Left atrial volume

Increased left atrial volume (LA) (Fig. 5, D) is a morphological marker of chronically increased diastolic filling pressures⁴³ and is an important mortality predictor⁴⁴. LA volume can also be increased in atrial fibrillation or significant mitral valve disease, therefore it is important to combine this parameter with the patient's clinical condition and with other echocardiographic markers of diastolic dysfunction³⁹.

Myocardial strain analysis

Myocardial strain can now be evaluated by echocardiography using speckle tracking, which can provide essential information regarding diastolic function³⁹, and may be a more reliable marker of diastolic dysfunction than the E/e' ratio⁴⁵.

Diastolic stress test

A great number of patients with diastolic dysfunction only develop symptoms during exercise. Therefore, it is important to evaluate LV filling pressures in response to exercise, by conducting a diastolic stress test.

This test can evaluate the E/e' ratio variation in response to exercise. While in individuals with normal relaxation, both E and e' velocities increase proportionally (keeping a normal E/e' ratio), in patients with diastolic dysfunction there is a progressive increase of the E/e' ratio with exercise⁴⁶.

In conclusion, although some limitations still exist⁴⁷, diastolic function can be reliably assessed by echocardiography, using an integrated step-by-step approach, starting with E/e' ratio evaluation. Moreover, diastolic dysfunction evaluation provides essential information for diagnosis, prognosis and management of patients with HF, particularly those with HFpEF⁴².

Misconception 7: there are effective strategies to treat HF with preserved EF

Probably the biggest misconception in HFpEF management is to think that there are effective therapeutic strategies for HFpEF, or to believe that such treatment may be similar to that used in systolic HF.

Firstly, despite its clinical and epidemiological significance, HFpEF treatment remains largely empirical and not evidence based. Unlike in SHF, few randomized clinical trials have been conducted in these patients.

Secondly, the few clinical trials conducted in HFpEF patients, only evaluated the effectiveness of renin-angiotensin system inhibitors. In all such studies the results were disappointing, since there was no survival benefit by using such agents. Hence, the use of other therapeutic agents in HFpEF can only be recommended theoretically or based on data obtained from observational studies.

Finally, in recent decades, the prognosis of HFpEF has remained unchanged over time, contrasting with the survival benefit observed in SHF patients⁶. This observation also demonstrates that HFpEF management strategies are still not appropriate.

Use of the renin-angiotensin system modulators

Contrary to systolic HF, in HFpEF blocking the renin-angiotensin system is less useful in terms of clinical events reduction or survival benefit, as demonstrated using perindopril (PEP-CHF trial)⁴⁸, irbesartan (I-PRESERVE)⁴⁹ or candesartan (CHARM-Preserved)⁵⁰.

Role of beta blockers in HFpEF

In theory, beta blockers (BB) have various potential benefits in HFpEF treatment: i) by reducing the heart rate they increase the duration of diastole and hence ventricular filling time; ii) they decrease myocardial oxygen requirements; iii) they lower blood pressure; and iv) they may induce regression of LVH. On the other hand, these beneficial effects may be partially mitigated since BB delay ventricular relaxation and reduce contractility¹⁶.

Although there are no clinical trials assessing BB efficacy in HFpEF, it is expected that these agents can be potentially beneficial, especially those with a vasodilator effect (e.g. carvedilol and nebivolol), because they can also reduce arterial stiffness.

Data from observational studies indicate that beta-blockers in HFPEF may reduce mortality⁵¹. Recently, a subanalysis derived from the SENIORS trial showed that in the subgroup of patients with EF > 35%, the benefits of this BB were similar, which suggests that the effectiveness of BB is not depend on ejection fraction⁵². With so many uncertainties, there is an urging need for a clinical trial to test the use of BB in HFpEF.

Aldosterone antagonists in HFpEF

The use of antagonists aldosterone in HFpEF can be beneficial, at least from a theoretical standpoint. Aldosterone acts both on the myocardium and vessels, promoting myocyte hypertrophy, fibrosis and collagen deposition, all of which may contribute to increased myocardial and arterial stiffness, contributing HFpEF progression⁵³. A small clinical trial demonstrated that spironolactone improved echocardiographic parameters of diastolic dysfunction⁵⁴. A randomized clinical trial - the TOPCAT study - is currently in progress aimed at assessing the role of aldosterone antagonists in HFPEF patients.

Other therapeutic strategies

Given so many uncertainties, only some general principles are recommended for HFpEF treatment¹: i) aggressive blood pressure control, to prevent the onset of HFpEF, to reduce the number of HF hospitalizations, to induce left ventricular hypertrophy regression and to improve ventricular-arterial coupling; ii) reduction of ventricular filling pressures, by restricting salt intake and administration of diuretics, which is particularly important since HFpEF patients are highly sensitive to changes in central volume and pre-load; iii) maintaining sinus rhythm, to preserve atrial contraction; iv) heart rate control, preventing tachycardia, which shortens diastole duration; and v) treatment of underlying comorbidities, using an integrated and multidisciplinary approach.

Potential new therapeutic targets in HFpEF

The future treatment for HFpEF is dependent on a better understanding of its pathophysiology and on multiple interventions on the various underlying physiopathological mechanisms. Due to the heterogeneous mechanisms that cause HFpEF, its treatment will always be multifactorial and individualized to each patient.

Assuming that changes in relaxation and increased stiffness are the main pathophysiological alterations in HFpEF, it is necessary to develop new therapeutic strategies that specifically target these alterations. Alagebrium, or ALT-177, is a new drug that breaks the crosslinks that form between advanced glycosylation endproducts, thereby improving diastolic function (by reducing ventricular stiffness), vascular function (by improving arterial distensibility), and ventricular-arterial coupling. Small clinical trials have shown promising results in HFpEF⁵⁵.

Given the importance of fibrosis in increasing ventricular stiffness, several studies are analyzing (with promising results) the antifibrotic effects of several growth factors, cytokines and signaling molecules⁵⁶.

In recent years, our research group has also contributed to clarifying the determinants of left ventricular passive properties, demonstrating that ventricular stiffness is not just a passive property, but that it can be actively modulated (and reduced) using neuro-hormonal manipulation (e.g. renin-angiotensin system and endothelin, among others), opening new therapeutic targets for ventricular stiffness reduction^57-60.

In HFpEF, ventricular relaxation should also be improved. As previously mentioned, relaxation is dependent on the uptake of calcium back into the sarcoplasmic reticulum by the action of SERCA_2A, which in turn is regulated by phospholamban⁶¹. Animal studies have shown that genetic transfer of SERCA_2A or modified phospholamban improves ventricular diastolic function^{62, 63}.

Given the beneficial effects of nitric oxide (NO) on endothelial, vascular and myocardial functions, type 5 phosphodiesterase inhibitors (e.g. sildenafil) may have a role in HF treatment, including in HFpEF⁶⁴. A clinical trial is currently in progress to assess this possibility.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any post-graduation program.

References

• 1. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology.Eur Heart J. 2008; 29 (19): 2388-442.
• 2. Tribouilloy C, Resinaru D, Mahjoub H, Souliére V, Levy F, Peltier M, et al. Prognosis of heart failure with preserved ejection fraction:a 5 year prospective population-based study. Eur Heart J. 2008; 29 (3): 339-4.
• 3. Bhatia RS, Tu J, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006; 355 (3): 260-9.
• 4. Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007; 50 (8): 768-77.
• 5. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure. Part I. Diagnosis, prognosis, and measurements of diastolic function. Circulation. 2002; 105 (11): 1387-93.
• 6. Owan TE, Hodge D, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006; 355 (3): 251-9.
• 7. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the ADHERE Database. J Am Coll Cardiol. 2006; 47 (1): 76-84.
• 8. Moutinho MA, Colucci FA, Alcoforado V, Tavares LR, Rachid MB, Rosa ML, et al. Heart failure with preserved ejection fraction and systolic dysfunction in the community. Arq Bras Cardiol. 2008; 90 (2): 132-7.
• 9. Brutsaert DL, De Keulenaer. Diastolic heart failure: a myth. Curr Opin Cardiol. 2006; 21 (3): 240-8.
• 10. De Keulenaer GW, Brutsaert D. The heart failure spectrum: time for a phenotype-oriented approach. Circulation. 2009; 119 (24): 3044-6.
• 11. Zille MR. Heart failure with preserved ejection fraction: is this DHF? J Am Coll Cardiol. 2003; 41 (9): 1519-22.
• 12. Lee DS, Gona P, Vasan RS, Larson MB, Benjamin EJ, Wang TJ, et al. Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the Framingham heart study of the NHLB Institute. Circulation. 2009; 119 (24): 3070-7.
• 13. Chen HH, Lainchbury J, Senni M, Bailey KR, Redfield MM. Diastolic heart failure in the community: clinical profile, natural history, therapy, and impact of proposed diagnostic criteria. J Card Fail. 2002; 8 (5): 279-87.
• 14. Zile MR, Baicu C, Bonnema DD, Diastolic heart failure: definitions and terminology. Prog Cardiovasc Dis. 2005; 47 (5): 307-13.
• 15. Leite-Moreira AF. Current perspectives in diastolic dysfunction and diastolic heart failure. Heart. 2006; 92 (5): 712-8.
• 16. Fontes-Carvalho R, Leite-Moreira AF. The pathophysiology of heart failure with preserved ejection fraction and its therapeutic implications. Rev Port Cardiol. 2009; 28 (1): 63-82.
• 17. van Heerebeek L, Borbely A, Niessen HW, Bronzwaer JG, van Der Velden J, Stienen GJ, et al. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006; 113 (16): 1966-73.
• 18. Borbély A, Falcao-Pires I, van Heerebeek L, Hamdani N, Edes I, Gavina C, et al. Hypophosphorylation of the Stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ Res. 2009; 104 (6): 780-6.
• 19. Ahmed SH, Clark L, Pennington WR, Webb CS, Bonnema DD, Leonardi AH, et al. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation. 2006; 113 (17): 2089-96.
• 20. Spinale FG, Coker M., Heung LJ, Bond BR, Gunasinghe HR, Etoht, et al. A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation. 2000; 102 (16): 1944-9.
• 21. Periasamy M, Jansen P. Molecular basis of diastolic dysfunction. Heart Fail Clin. 2008; 4 (1): 13-21.
• 22. Hunt SA, Abraham W, Chin MH, Feldman AM, Francis S, Ganiats TG, et al. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the ACC Foundation/AHA Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation.J Am Coll Cardiol, 2009; 53 (15): e1-e90.
• 23. Zile MR, Baicu C, Gaasch WH. Diastolic heart failure: abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004; 19 (19): 1953-9.
• 24. Paulus W, Tchoppe C, Sanderson J, Rusconi C, Flachskampf FE, Rademakers FE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007; 28 (20): 2539-50.
• 25. Redfield MM, Jacobsen S, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. 2003; 289 (2): 194-202.
• 26. Kuznetsova T, Herbotz L, Lopez B, Jin Y, Richart T, Thys L, et al. Prevalence of left ventricular diastolic dysfunction in a general population. Circ Heart Fail. 2009; 2 (2): 105-12.
• 27. Maurer MS, King D, El-Khoury R, Packer M, Burkhoff D. Left heart failure with a normal ejection fraction: identification of different pathophysiologic mechanisms. J Card Fail. 2005; 11 (3): 177-87.
• 28. Maeder M, Kaye D, Heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol. 2009; 53 (11): 905-18.
• 29. Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation. 2003; 107 (5): 714-20.
• 30. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Heart Fail Clin. 2008; 4 (1): 23-36.
• 31. Borlaug BA, Melenovski V, Russell SD, Kessler K, Pacak K, Becker LC, et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation. 2006; 114 (20): 2138-47.
• 32. Maurer MS, Burkhoff D, Fried LP, Gottdiener J, King DL, Kitzman DW. Ventricular structure and function in hypertensive participants with heart failure and a normal ejection fraction: the Cardiovascular Health Study. J Am Coll Cardiol. 2007; 49 (9): 972-81.
• 33. Wang J, Khoury D, Yue Y, Torre-Amione G, Nagueh SF. Preserved left ventricular twist and circumferential deformation, but depressed longitudinal and radial deformation in patients with diastolic heart failure. Eur Heart J. 2008; 29 (10): 1283-9.
• 34. Tan YT, Wenzelburger F, Lee E, Heatlie G, Leyva F, Patel K, et al. The pathophysiology of heart failure with normal ejection fraction: exercise echocardiography reveals complex abnormalities of both systolic and diastolic ventricular function involving torsion, untwist, and longitudinal motion. J Am Coll Cardiol. 2009; 54 (10): 36-46.
• 35. Westermann D, Kasner M, Steendijk P, Spillmann F, Riead A, Weitmann K, et al. Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation. 2008; 117 (16): 2051-60.
• 36. Kitzman DW, Higginbotham M, Cobb FR, Sheikh KH, Sullivan MJ. Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol. 1991; 17 (5): 1065-72.
• 37. Bruch C, Gradaus R, Gunia S, Breithardt G, Wichter T. Doppler tissue analysis of mitral annular velocities: evidence for systolic abnormalities in patients with diastolic heart failure. J Am Soc Echocardiogr. 2003; 16 (10): 1031-6.
• 38. Yip G, Wang M, Zhang Y, Fung JW, Ho PY, Sanderson JE. Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: time for a redefinition? Heart Fail Clin. 2002; 87 (2): 121-5.
• 39. Nagueh SF, Appleton C, Gillebert TC, Marino PN, Oh JK, Smiseth AO, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr. 2009; 10 (2): 165-93.
• 40. Mesquita E, Jorge A. Heart failure with normal ejection fraction: new diagnostic criteria and pathophysiological advances. Arq Bras Cardiol. 2009; 93 (2): 180-7.
• 41. Somaratne JB, Whalley G, Gamble GD, Doughty R. Restrictive filling pattern is a powerful predictor of heart failure events post acute myocardial infarction and in established heart failure: a literature-based meta-analysis. J Card Fail. 2007; 13 (5): 346-52.
• 42. Little WC, Oh J. Echocardiographic evaluation of diastolic function can be used to guide clinical care. Circulation. 2009; 120 (9): 802-9.
• 43. Lester SJ, Tajik A, Nishimura RA, Oh JK, Khanderia BK, Seward JB. Unlocking the misteries of diastolic function. J Am Coll Cardiol. 2008; 51 (7): 679-89.
• 44. Douglas P. The left atrium: a biomarker of chronic diastolic dysfunction and cardiovascular disease risk. J Am Coll Cardiol. 2003; 42 (7): 1206-7.
• 45. Dokainish H, Sengupta R, Pillai M, Bobek J, Lakkis N. Usefulness of new diastolic strain and strain rate indexes for the estimation of left ventricular filling pressure. Am J Cardiol. 2008; 101 (10): 1504-9.
• 46. Ha JW, Oh JK, Pellikka PA, Ommen SR, Stussy VL, Bailey KR, et al. Diastolic stress echocardiography: a novel noninvasive diagnostic test for diastolic dysfunction using supine bicycle exercise Doppler echocardiography. J Am Soc Echocardiogr. 2005; 18 (1): 63-8.
• 47. Tschöpe C, Paulus W. Is echocardiographic evaluation of diastolic function useful in determining clinical care? Doppler echocardiography yields dubious estimates of left ventricular diastolic pressures. Circulation. 2009; 120 (9): 810-20.
• 48. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor I. PEP-CHF Investigators. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006; 27 (19): 2338-45.
• 49. Massie BM, Carson P, McMurray JJ, Komajda M, McKelvie R, Zile MR. I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008; 359 (23): 2456-67.
• 50. Yusuf S, Pfeffer M, Swedberg K, Granger CB, Held P, McMurray JJ, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003; 362 (9386): 777-81.
• 51. Dobre D, van Veldhuisen D, DeJongste MJ, Lucas C, Cleuren G, Sanderman R, et al. Prescription of beta-blockers in patients with advanced heart failure and preserved left ventricular ejection fraction: clinical implications and survival. Eur J Heart Fail. 2007; 9 (3): 280-6.
• 52. van Veldhuisen DJ, Cohen-Solal A, Böhm M, Anker SD, Babalis D, Roughton M, et al. SENIORS Investigators. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: data from SENIORS. J Am Coll Cardiol. 2009; 53 (23): 2150-8.
• 53. Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001; 345 (23): 1689-97.
• 54. Mottram PM, Haluska B, Leano R, Cowley D, Stowasser M, Marwick TH. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation. 2004; 110 (5): 558-65.
• 55. Little WC, Zile M, Kitzman DW, Hundley WG, O'Brien TX, Degroof RC. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail. 2005; 11 (3): 191-5.
• 56. Kaye DM, Krum H. Drug discovery for heart failure: a new era or the end of the pipeline? Nat Rev Drug Discov. 2007; 6 (2): 127-39.
• 57. Leite-Moreira AF, Castro-Chaves P, Pimentel-Nunes P, Lima-Carneiro A, Guerra MS, Soares JB, et al. Angiotensin II acutely decreases myocardial stiffness: a novel AT1, PKC and Na+/H+ exchanger-mediated effect. Br J Pharmacol. 2006; 147 (6): 690-7.
• 58. Leite-Moreira AF, Bras-Silva C, Pedrosa CA, Rocha-Sousa AA. ET-1 increases distensibility of acutely loaded myocardium: a novel ETA and Na+/H+ exchanger mediated effect. Am J Physiol Heart Circ Physiol. 2003; 284 (4): 1332-9.
• 59. Castro-Chaves P, Fontes-Carvalho R, Pintalhao M, Pimentel-Nunes P, Leite-Moreira AF. Angiotensin II-induced increase in myocardial distensibility and its modulation by the endocardial endothelium in the rabbit heart. Exp Physiol. 2009; 94 (6): 665-74.
• 60. Ladeiras-Lopes R, Ferreira-Martins J, Leite-Moreira AF. Acute neurohumoral modulation of diastolic function. Peptides. 2009; 30 (2): 419-25.
• 61. Periasamy M, Jansen PM. Molecular basis of diastolic dysfunction. Heart. Fail Clin. 2008; 4 (1): 13-21.
• 62. Gupta D, Palma J, Molina E, Gaughan JP, Long W, Houser S, et al. Improved exercise capacity and reduced systemic inflammation after adenoviral-mediated SERCA-2a gene transfer. J Surg Res. 2008; 145 (2): 257-65.
• 63. Schmidt U, del Monte F, Miyamoto MI, Matsui T, Gwathmey JK, Rosenzweig A, et al. Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca(2þ)-ATPase. Circulation. 2000; 101 (7): 790-6.
• 64. Goldsmith SR. Type 5 Phosphodiesterase inhibition in heart failure: the next step. J Am Coll Cardiol. 2007; 50 (22): 2145-7.

Heart failure with preserved ejection fraction: fighting misconceptions for a new approach

Ricardo Fontes-Carvalho^I,II; Adelino Leite-Moreira^I,III

Publication Dates

• Publication in this collection
  03 Oct 2011
• Date of issue
  June 2011

History

• Received
  01 Dec 2009
• Accepted
  24 Mar 2010
• Reviewed
  17 Feb 2010